The present invention relates to methods of synthesizing organic compounds, and more particularly to methods of asymmetrically synthesizing optically active pharmaceutical compounds and their intermediates.
Androgen deprivation is a common treatment for persons with prostate cancer. Various non-steroidal antiandrogens are known for use in the treatment of prostate cancer. For example, bicalutamide, which may be among the most commonly used non-steroidal antiandrogens in the world, is typically used in the treatment of prostate cancer. Bicalutamide is commercially available as Casodex(copyright) (bicalutamide) from Zeneca Pharmaceuticals.
The chemical name of bicalutamide is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide,(+xe2x88x92). The structural formula of bicalutamide is: 
The xcex2-carbon atom in the propanamide is a chiral carbon. As a result, bicalutamide is an optically active compound.
Optically active compounds have the ability to rotate the plane of polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (xe2x88x92) are used to denote the optical rotation of the compound (i.e., the direction in which a plane of polarized light is rotated by the optically active compound). The l or (xe2x88x92) prefix indicates that the compound is levorotatory (i.e., rotates the plane of polarized light to the left or counterclockwise) while the d or (+) prefix means that the compound is dextrarotatory (i.e., rotates the plane of polarized, light to the right or clockwise). The sign of optical rotation, (xe2x88x92) and (+), is not related to the absolute configuration of the molecule, R and S.
Optically active compounds, such as bicalutamide, exist as a pair of stereoisomers that are identical with the notable exception that they are non-superimposable mirror images of one another. A specific stereoisomer, such as the R isomer, may be referred to as an enantiomer. A mixture of R and S enantiomers may be referred to as a racemic mixture.
Bicalutamide, is presently commercially available as a racemic mixture. The racemic mixture of bicalutamide may be synthesized by various methods including, for example, the methods described in U.S. Pat. No. 4,636,505 to Tucker. Tucker further describes various derivatives and analogs of bicalutamide having antiandrogenic properties. Tucker, however, does not disclose or suggest methods for asymmetrically synthesizing enantiomers of Casodex(copyright) (bicalutamide) and/or its intermediates.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic mixtures of Casidex(copyright) (bicalutamide) using methods as described in U.S. Pat. No. 4,636,505 to Tucker, and obtaining the (xe2x88x92) isomer of Casidex(copyright) (bicalutamide) by resolution of the enantiomers of Casidex(copyright) (bicalutamide) or of intermediates thereto using fractional crystallization or chromatography of diastereomeric esters of chiral acids. Gray notes that other standard methods of resolution such as simple crystallization and chromatographic resolution can also be used. Gray does not disclose or suggest methods of asymmetrically synthesizing enantiomers of Casodex(copyright) (bicalutamide) and/or its derivatives and/or intermediates.
In Howard Tucker et al., Resolution of the Nonsteroidal Antiandrogen 4xe2x80x2-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)-propioanilide and the Determination of the Absolute Configuration of the Active Enantiomer, 31 J. Med. Chem. 885-887 (1988), the authors propose an asymmetric synthesis of (S)-Casodex(copyright) (bicalutamide) using the N-methacrylamide of (S)-proline as a starting material. The proposed reaction scheme is as follows: 
The authors state that this approach is not suitable for the general synthesis of the active enantiomers of analogous anti-androgens, which would require the inaccessible and expensive (R)-proline as a starting material.
U.S. Pat. No. 6,019,957 to Miller et al. proposes an asymmetric synthesis of (R)-Casodex(copyright) (bicalutamide) using (R)-proline as a starting material. The proposed reaction scheme is as follows: 
As noted above, (R)-proline is an inaccessible and expensive starting material. It would be desirable to provide more cost effective methods for asymmetrically synthesizing enantiomers of Casodex(copyright) (bicalutamide) and/or its derivatives and/or intermediates that do not rely on (R)-proline as a starting material.
Embodiments of the present invention provide methods for asymmetrically synthesizing enantiomers of Casodex(copyright) (bicalutamide) and/or its intermediates. Asymmetric synthesis methods according to embodiments of the present invention are more cost effective than conventional methods. For example, asymmetric synthesis methods according to embodiments of the present invention react 4-fluorobenzenethiol with the bromolactone of Formula 1 or 2 above. By reacting the 4-fluorobenzenethiol with the bromolactone prior to hydrolyzing the bromolactone instead of hydrolyzing the bromolactone and then reacting the 4-fluorobenzenethiol with the resulting acid as proposed above, improved separation of the reaction products and thus higher yields may be provided. Furthermore, asymmetric synthesis methods according to embodiments of the present invention produce (R)-Casodex(copyright) (bicalutamide) and/or its intermediates using (S)-citramalic acid (2-hydroxy-2-methylbutanedioic acid) as a starting material, which may be more cost effective than the conventional scheme, which uses the inaccessible and expensive (R)-proline as a starting material.
According to embodiments of the present invention, methods of asymmetrically synthesizing an enantiomer of an acylanalide such as Casodex(copyright) (bicalutamide) or its derivatives are provided. The methods include contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I: 
wherein
R1 is alkyl or haloalkyl having up to 4 carbons;
R2 is alkyl having up to 6 carbon atoms; and
R3 is CH2OR4 where R4 is hydrogen or benzyl, C(O)CH3, or C(O)OR5 where R5 is hydrogen or alkyl;
with a compound having a structure of Formula II:
R7xe2x80x94R6xe2x80x94X1Hxe2x80x83xe2x80x83Formula II
xe2x80x83wherein
R6 is a direct link or alkyl having up to 6 carbon atoms;
R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons; or R7 is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; or R7 is naphthyl; or R7 is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and
X1 is oxygen, sulfur, sulphinyl (xe2x80x94SOxe2x80x94), sulphonyl (xe2x80x94SO2xe2x80x94), imino (xe2x80x94NHxe2x80x94) or alkylimino (xe2x80x94NR8xe2x80x94) where R8 is alkyl having up to 6 carbon atoms;
under conditions sufficient to provide a compound having the structure of Formula III: 
wherein X2 is oxygen, sulfur, sulphinyl (xe2x80x94SOxe2x80x94), sulphonyl (xe2x80x94SO2xe2x80x94), imino (xe2x80x94NHxe2x80x94), oxidized imino alkylimino (xe2x80x94NR8xe2x80x94) where R8 is alkyl having up to 6 carbon atoms, or oxidized alkylimino. The method further includes treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of Casodex(copyright) (bicalutamide) or a pure enantiomer of a Casodex(copyright) (bicalutamide) derivative. In preferred embodiments, R1 is methyl, R2 is methylene, R6 is a direct link, R7 is 4-fluorophenyl, X1 is sulfur, the compound of Formula II is 4-fluorobenzenethiol, and X2 is sulphonyl.
In other embodiments according to the present invention, the compound having a ring structure is a compound of Formula IV: 
wherein
R9 is hydrogen, or straight, branched or cyclic alkyl;
R10 is straight or branched alkyl, aryl, or R11X34, where R11 is alkyl and X4 is alkyl, halogen or aryl; and
X3 is a leaving group.
The compound of Formula IV is contacted with the compound of Formula II under conditions sufficient to provide a compound having the structure of Formula V: 
In preferred embodiments, R1 is methyl and R2 is methylene. In particularly preferred embodiments, citramalic acid is used as a starting material to provide a compound having the structure of Formula IV. The citramalic acid may be either the (R) or the (S) enantiomer; however, it is preferable to use the (S)-enantiomer of citramalic acid because it may be more readily available and thus, unlike (R)-proline, may be a relatively inexpensive starting material in the synthesis of arylanilides such as Casodex(copyright) (bicalutamide) and/or its derivatives. Furthermore, the more active form of Casodex(copyright) (bicalutamide) ((R)-Casodex(copyright) (bicalutamide)) can be synthesized according to methods of the present invention using (S)-citramalic acid.
In still other embodiments according to the present invention, the compound having a ring structure is a compound of Formula VIII: 
wherein X5 is a leaving group. The compound of Formula VIII is contacted with the compound of Formula II under conditions sufficient to provide a compound having the structure of Formula IX: 
In yet other embodiments of the present invention, the compound having a ring structure is a compound of Formula XI: 
The compound of Formula XI is contacted with the compound of Formula II under conditions sufficient to provide a compound having the structure of Formula XII: 
In preferred embodiments, the compound of Formula III is treated with a compound having the structure of Formula XIII: 
wherein
R13 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;
R14 is cyano, cabamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of having up to 4 carbon atoms; or phenylthio, phenylsulphinyl or phenylsulphonyl; and
R15 is hydrogen or halogen;
under conditions sufficient to provide a compound of Formula XIV: 
wherein X2 is oxygen, sulfur, sulphinyl (xe2x80x94SOxe2x80x94), sulphonyl (xe2x80x94SO2xe2x80x94), imino (xe2x80x94NHxe2x80x94), oxidized imino alkylimino (xe2x80x94NR8xe2x80x94) where R8 is alkyl having up to 6 carbon atoms, or oxidized alkylimino. In preferred embodiments, the compound of Formula XIII is 4-amino-2-trifluoromethylbenzonitrile, and the compound of Formula XIV is Casodex(copyright) (bicalutamide).
Asymmetric synthesis methods according to the present invention may provide pure enantiomers of Casodex(copyright) (bicalutamide) and/or its intermediates in a more cost effective manner than conventional methods. For example, as noted above, conventional methods that attempt to provide the more active (R)-enantiomer of Casodex(copyright) (bicalutamide) do so either by synthesizing ester derivatives of the racemic mixture and then separating the (R) enantiomer from the (S) enantiomer to produce a Casodex(copyright) (bicalutamide) mixture having a higher concentration of (R) enantiomer than (S) enantiomer or by asymmetrically synthesizing the (R)-enantiomer using the inaccessible and expensive (R)-proline as a starting material. By asymmetrically synthesizing the (R) enantiomer of Casodex(copyright) (bicalutamide) rather than synthesizing and then separating a racemic mixture, methods according to embodiments of the present invention eliminate the economic waste associated with discarding the (S) enantiomer. Furthermore, according to embodiments of the present invention, (R)-Casodex(copyright) (bicalutamide) is asymmetrically synthesized using the readily available (S)-citramalic acid as a starting material rather than the inaccessible and expensive (R)-proline.